Enhanced HER-2/neu-specific antitumor immunity by cotransduction of mouse dendritic cells with two genes encoding HER-2/neu and alpha tumor necrosis factor

Chen, Zhuang; Huang, Hui; Chang, Tim; Carlsen, Svein A.; Saxena, Anurag; Marr, Robert A.; Xing, Zhou; Xiang, Jim

doi:10.1038/sj.cgt.7700498

Cited by 33 publications

(34 citation statements)

References 31 publications

(24 reference statements)

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“…We also demonstrated that the in vitro T TNF cell cytotoxicity is mainly mediated by perforin secretion, which is consistent with our previous reports. 33,34 In this study, we also analyzed the therapeutic effect of engineered OVA-specific CD8 þ T TNF cells in mice bearing either 12-day lung micrometastasis or solid tumors (B5 mm in diameter) secreting IL-10. We showed that the engineered CD8 þ T TNF cells secreting the transgene-coded human TNF-a eradicated the IL-10-secreting B16 OVA/ILÀ10 lung metastasis in all 10/10 mice, whereas the control DC OVA -activated CD8 þ T (T control ) and DC OVA -activated CD8 þ T (T þ rTNF) cells with further culturing in the medium containing the recombinant human TNF-a eliminated lung metastasis in only 2/10 and 1/10 mice, respectively, indicating that the engineered CD8 þ T TNF cells have enhanced in vivo therapeutic effect on the IL-10-secreting B16 OVA/ILÀ10 lung metastasis.…”

Section: Discussionmentioning

confidence: 99%

“…The above DC OVA -activated CD8 þ T cells were further incubated with the fiber-modified FMAdVTNF-a and the control FMAdV at MOI of 100. 34 Following the viral adsorption for 1 h at 371, the T-cell culture medium was replaced with DMEM/10% FCS/IL-2 (10 U/ml), and the T cells were incubated for another 24 h at 371. CD8 þ T cells transfected with FMAdVTNF and the control FMAdV were referred to as CD8 þ T TNF and CD8 þ Tcontrol cells, respectively.…”

Section: Engineering Cd8 þ T Tnf Cells With Fmadvtnfmentioning

confidence: 99%

“…Approximately 1 Â 10 4 labeled target cells per triplicate well were mixed with effector cells at various E:T cell ratios, and then incubated for 6 h. For testing the killing mechanism, the effector cells were pre-incubated with CMA (1 mM) and emetin (5 mM) for 2 h to prevent perforin (CMA)-or Fas/FasL interaction (emetin)-mediated cytotoxicity. 34 The percentage of specific lysis was calculated as: 100 Â ((experimental count per minute (cpm)Àspontaneous cpm)/(maximal cpmÀspontaneous cpm)). Spontaneous cpm release in the absence of E cells was o10% of specific lysis.…”

Section: T-cell Cytotoxicity Assaymentioning

confidence: 99%

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Engineered CD8+ cytotoxic T cells with fiber-modified adenovirus-mediated TNF-α gene transfection counteract immunosuppressive interleukin-10-secreting lung metastasis and solid tumors

Shi

Chan

et al. 2007

Cancer Gene Ther

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T-cell suppression derived from tumor-secreted immunosuppressive interleukin (IL)-10 becomes a major barrier to CD8 þ T-cell immunotherapy of tumors. Tumor necrosis factor-alpha (TNF-a) is a multifunctional cytokine capable of activating T and dendritic cells (DCs) and counteracting IL-10-mediated DC inhibition and regulatory T-cell-mediated immune suppression. In this study, we constructed a recombinant adenovirus MF AdVTNF with fiber-gene modified by RGD insertion into the viral knob's H1 loop and a melanoma cell line B16 OVA/ILÀ10 engineered to express ovalbumin (OVA) and to secrete IL-10 (2.2 ng/ml/10 6 cells/24 h). We transfected OVA-specific CD8 þ T cells with MF AdVTNF, and found a fivefold increase in transgene human TNF-a secretion (4.3 ng/ ml/10 6 cells/24 h) by the engineered CD8 þ T TNF cells transfected with MF AdVTNF, compared to that (0.8 ng/ml/10 6 cells/24 h) by CD8 þ T cells transfected with the original AdVTNF without viral fiber modification. The engineered CD8 þ T TNF cells exhibited enhanced cytotoxicity and elongated survival in vivo after adoptive transfer. TNF-a derived from both the donor CD8 þ T cells and the host cells plays an important role in donor CD8 þ T-cell survival in vivo after adoptive transfer. We also demonstrated that the transfected B16 OVA/ILÀ10 tumor cells secreting IL-10 are more resistant to in vivo CD8 þ T-cell therapy than the original B16 OVA tumor cells without IL-10 expression. Interestingly, the engineered CD8 þ T TNF cells secreting transgene-coded TNF-a, but not the control CD8 þ T control cells without any transgene expression eradicated IL-10-secreting 12-day lung micrometastasis in all 10/10 mice and IL-10-secreting solid tumors (B5 mm in diameter) in 6/10 mice. Transfer of the engineered CD8 þ T TNF cells further induced both donor-and host-derived memory CD8 þ T cells, leading to a stronger long-term antitumor immunity against the IL-10-secreting B16 OVA/ILÀ10 tumor cell challenges. Therefore, CD8 þ T cells engineered to secrete TNF-a may be useful when designing strategies for adoptive T-cell therapy of solid tumors.

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Section: Discussionmentioning

confidence: 99%

Section: Engineering Cd8 þ T Tnf Cells With Fmadvtnfmentioning

confidence: 99%

Section: T-cell Cytotoxicity Assaymentioning

confidence: 99%

See 1 more Smart Citation

Engineered CD8+ cytotoxic T cells with fiber-modified adenovirus-mediated TNF-α gene transfection counteract immunosuppressive interleukin-10-secreting lung metastasis and solid tumors

Shi

Chan

et al. 2007

Cancer Gene Ther

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“…As CD4 þ helper T (Th) cells triggered by the complexes of MHC class II and tumor peptide on DCs play an important role in facilitating antitumor immunity by augmentation of the CTL responses, 21 DCs have been engineered with recombinant adenoviral vectors (AdVs) to express HER-2/neu Ag containing both MHC class I-and II-restricted tumor peptides. 22,23 It has been demonstrated that these engineered DCs can elicit both HER-2/neu-specific CTL and Th clones. 24 and stimulate antitumor immunity against challenge of HER-2/neu-positive tumor cells in vivo 22,23 leading to phaseI/II clinical trials.…”

Section: Introductionmentioning

confidence: 99%

“…22,23 It has been demonstrated that these engineered DCs can elicit both HER-2/neu-specific CTL and Th clones. 24 and stimulate antitumor immunity against challenge of HER-2/neu-positive tumor cells in vivo 22,23 leading to phaseI/II clinical trials. 25,26 However, there are limited studies evaluating the use of HER-2/neutargeted DC-based vaccination in rat HER-2/neu-gene transgenic (Tg) mice with self HER-2/neu tolerance.…”

Section: Introductionmentioning

confidence: 99%

Vaccination of fiber-modified adenovirus-transfected dendritic cells to express HER-2/neu stimulates efficient HER-2/neu-specific humoral and CTL responses and reduces breast carcinogenesis in transgenic mice

et al. 2008

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HER-2/neu transgene-modified dendritic cell (DC)-based vaccines are potent at eliciting HER-2/neu-specific antitumor immunity. In this study, we constructed a recombinant adenovirus RGD AdVneu with fiber gene modified by RGD insertion into the viral knob's H1 loop. We transfected DCs with RGD AdVneu, and assessed/compared HER-2/neu-specific humoral and cytotoxic T lymphocyte (CTL) responses and antitumor immunity derived from the original AdVneu-transfected DCs (DCneu1) and RGD AdVneu-transfected DCs (DCneu2). We demonstrated that DCneu2 displayed increased HER-2/neu expression by 8.3-fold compared to DCneu1. We also demonstrated that DCneu2 vaccination induced stronger HER-2/neu-specific humoral and CTL immune responses than DCneu1 vaccination. DCneu2 vaccination protected all the mice from HER-2/neu-expressing Tg1-1 tumor cell challenge in wild-type FVB/NJ mice, compared to a partial protection in DCneu1-immunized mice. In addition, DCneu2 vaccination also significantly delayed tumor growth than DCneu1 immunization (Po0.05) in Tg FVBneuN mice. Three immunizations of DCneu2 starting at the mouse age of 2 months also significantly delayed breast cancer development in Tg mice compared to DCneu2 vaccine (Po0.05). Importantly, DCneu2 vaccine reduced breast carcinogenesis by 9% in Tg mice with self HER-2/neu tolerance. Therefore, vaccination of fiber-modified adenovirus-transfected DCs to enhance expression of tumor antigens such as HER-2/neu is likely representative of a new direction in DC-based vaccine of breast cancer.

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Influenza virus‐like particles engineered by protein transfer with tumor‐associated antigens induces protective antitumor immunity

Patel

Vartabedian

Kim

et al. 2015

Biotech & Bioengineering

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Delivery of antigen in particulate form using either synthetic or natural particles induces stronger immunity than soluble forms of the antigen. Among naturally occurring particles, virus-like particles (VLPs) have been genetically engineered to express tumor-associated antigens (TAAs) and have shown to induce strong TAA-specific immune responses due to their nano-particulate size and ability to bind and activate antigen-presenting cells. In this report, we demonstrate that influenza VLPs can be modified by a protein transfer technology to express TAAs for induction of effective antitumor immune responses. We converted the breast cancer HER-2 antigen to a glycosylphosphatidylinositol (GPI)-anchored form and incorporated GPI-HER-2 onto VLPs by a rapid protein transfer process. Expression levels on VLPs depended on the GPI-HER-2 concentration added during protein transfer. Vaccination of mice with protein transferred GPI-HER-2-VLPs induced a strong Th1 and Th2-type anti-HER-2 antibody response and protected mice against a HER-2-expressing tumor challenge. Soluble form of GPI-HER-2 induced only a weak Th2 response under similar conditions. These results suggest that influenza VLPs can be enriched with TAAs by protein transfer to develop effective VLP-based subunit vaccines against cancer without chemical or genetic modifications and thus preserve the immune stimulating properties of VLPs for easier production of antigen-specific therapeutic cancer vaccines.

show abstract

Enhanced HER-2/neu-specific antitumor immunity by cotransduction of mouse dendritic cells with two genes encoding HER-2/neu and alpha tumor necrosis factor

Cited by 33 publications

References 31 publications

Engineered CD8+ cytotoxic T cells with fiber-modified adenovirus-mediated TNF-α gene transfection counteract immunosuppressive interleukin-10-secreting lung metastasis and solid tumors

Engineered CD8+ cytotoxic T cells with fiber-modified adenovirus-mediated TNF-α gene transfection counteract immunosuppressive interleukin-10-secreting lung metastasis and solid tumors

Vaccination of fiber-modified adenovirus-transfected dendritic cells to express HER-2/neu stimulates efficient HER-2/neu-specific humoral and CTL responses and reduces breast carcinogenesis in transgenic mice

Influenza virus‐like particles engineered by protein transfer with tumor‐associated antigens induces protective antitumor immunity

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